NK cell–based immunotherapies have been gaining traction in the clinic for treatment of cancer. IL-15 is currently being used in number of clinical trials to improve NK cell expansion and function. The objective of this study is to evaluate the effect of repetitive IL-15 exposure on NK cells. An in vitro model in which human NK cells are continuously (on on on) or intermittently (on off on) treated with IL-15 was used to explore this question. After treatment, cells were evaluated for proliferation, survival, cell cycle gene expression, function, and metabolic processes. Our data indicate that continuous treatment of NK cells with IL-15 resulted in decreased viability and a cell cycle arrest gene expression pattern. This was associated with diminished signaling, decreased function both in vitro and in vivo, and reduced tumor control. NK cells continuously treated with IL-15 also displayed a reduced mitochondrial respiration profile when compared with NK cells treated intermittently with IL-15. This profile was characterized by a decrease in the spare respiratory capacity that was dependent on fatty acid oxidation (FAO). Limiting the strength of IL-15 signaling via utilization of an mTOR inhibitor rescued NK cell functionality in the group continuously treated with IL-15. The findings presented here show that human NK cells continuously treated with IL-15 undergo a process consistent with exhaustion that is accompanied by a reduction in FAO. These findings should inform IL-15–dosing strategies in NK cell cancer immunotherapeutic settings.
Martin Felices, Alexander J. Lenvik, Ron McElmurry, Sami Chu, Peter Hinderlie, Laura Bendzick, Melissa A. Geller, Jakub Tolar, Bruce R. Blazar, Jeffrey S. Miller
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Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells
M Daher, R Basar, E Gokdemir, N Baran, N Uprety, AK Cortes, M Mendt, LN Kerbauy, PP Banerjee, M Shanley, N Imahashi, L Li, FL Lim, M Fathi, A Rezvan, V Mohanty, Y Shen, H Shaim, J Lu, G Ozcan, E Ensley, M Kaplan, V Nandivada, M Bdiwi, S Acharya, , X Wan, D Mak, E Liu, XR Jiang, S Ang, L Muniz-Feliciano, Y Li, J Wang, S Kordasti, N Petrov, N Varadarajan, D Marin, L Brunetti, RJ Skinner, S Lyu, L Silva, R Turk, MS Schubert, GR Rettig, MS McNeill, G Kurgan, MA Behlke, H Li, NW Fowlkes, K Chen, M Konopleva, RE Champlin, EJ Shpall, K Rezvani |
Blood | 2021 |
Epitranscriptomic Approach: To Improve the Efficacy of ICB Therapy by Co-Targeting Intracellular Checkpoint CISH
S Kumar, P Sarthi, I Mani, MU Ashraf, MH Kang, V Kumar, YS Bae |
Cells | 2021 |
A robust platform for expansion and genome editing of primary human natural killer cells
RS Huang, MC Lai, HA Shih, S Lin |
Journal of Experimental Medicine | 2021 |
The Effect of Unconventional Cytokine Combinations on NK-Cell Responses to Viral Infection
DE Ochayon, SN Waggoner |
Frontiers in immunology | 2021 |
Cytokines Orchestrating the Natural Killer-Myeloid Cell Crosstalk in the Tumor Microenvironment: Implications for Natural Killer Cell-Based Cancer Immunotherapy
S Gaggero, K Witt, M Carlsten, S Mitra |
Frontiers in immunology | 2021 |
Chronic IL-15 Stimulation and Impaired mTOR Signaling and Metabolism in Natural Killer Cells During Acute Myeloid Leukemia
B Bou-Tayeh, V Laletin, N Salem, S Just-Landi, J Fares, R Leblanc, M Balzano, YM Kerdiles, G Bidaut, O Hérault, D Olive, M Aurrand-Lions, T Walzer, JA Nunès, C Fauriat |
Frontiers in immunology | 2021 |
Revisiting the Role of Natural Killer Cells in Non-Alcoholic Fatty Liver Disease
ML Martínez-Chantar, TC Delgado, N Beraza |
Frontiers in immunology | 2021 |
Optimising NK cell metabolism to increase the efficacy of cancer immunotherapy
C Choi, DK Finlay |
Stem Cell Research & Therapy | 2021 |
An Alternative Cell Therapy for Cancers: Induced Pluripotent Stem Cell (iPSC)-Derived Natural Killer Cells
LJ Hsu, CL Liu, ML Kuo, CN Shen, CR Shen |
Biomedicines | 2021 |
CAR-NK Cells in the Treatment of Solid Tumors
E Wrona, M Borowiec, P Potemski |
International journal of molecular sciences | 2021 |
AI-guided discovery of the invariant host response to viral pandemics
D Sahoo, GD Katkar, S Khandelwal, M Behroozikhah, A Claire, V Castillo, C Tindle, MK Fuller, S Taheri, TF Rogers, N Beutler, SI Ramirez, SA Rawlings, V Pretorius, DM Smith, DR Burton, LE Alexander, J Duran, S Crotty, JM Dan, S Das, P Ghosh |
EBioMedicine | 2021 |
Selection, Expansion, and Unique Pretreatment of Allogeneic Human Natural Killer Cells with Anti-CD38 Monoclonal Antibody for Efficient Multiple Myeloma Treatment
B Motais, S Charvátová, Z Walek, M Hrdinka, R Smolarczyk, T Cichoń, J Czapla, S Giebel, M Šimíček, T Jelínek, T Ševčíková, J Sobotka, Z Kořístek, R Hájek, JR Bagó |
Cells | 2021 |
Enhancing a Natural Killer: Modification of NK Cells for Cancer Immunotherapy
R Islam, A Pupovac, V Evtimov, N Boyd, R Shu, R Boyd, A Trounson |
Cells | 2021 |
iPSC-Derived Natural Killer Cells for Cancer Immunotherapy
P Karagiannis, SI Kim |
Molecules and Cells | 2021 |
Short-course IL-15 given as a continuous infusion led to a massive expansion of effective NK cells: implications for combination therapy with antitumor antibodies
SP Dubois, MD Miljkovic, TA Fleisher, S Pittaluga, J Hsu-Albert, BR Bryant, MN Petrus, LP Perera, JR Müller, JH Shih, TA Waldmann, KC Conlon |
Journal for ImmunoTherapy of Cancer | 2021 |
Time-resolved systems immunology reveals a late juncture linked to fatal COVID-19
C Liu, AJ Martins, WW Lau, N Rachmaninoff, J Chen, L Imberti, D Mostaghimi, DL Fink, PD Burbelo, K Dobbs, OM Delmonte, N Bansal, L Failla, A Sottini, E Quiros-Roldan, KL Han, BA Sellers, F Cheung, R Sparks, TW Chun, S Moir, MS Lionakis, C Rossi, HC Su, DB Kuhns, JI Cohen, LD Notarangelo, JS Tsang, MS Abers, R Apps, M Bosticardo, P Milanez-Almeida, MP Mulè, E Shaw, Y Zhang, F Castelli, ML Muiesan, G Tomasoni, F Scolari, A Tucci |
Cell | 2021 |
Interleukin-15 in Outcomes of Pregnancy
SM Gordon |
International journal of molecular sciences | 2021 |
PRDX-1 Supports the Survival and Antitumor Activity of Primary and CAR-Modified NK Cells under Oxidative Stress
Klopotowska M, Bajor M, Graczyk-Jarzynka A, Kraft A, Pilch Z, Zhylko A, Firczuk M, Baranowska I, Lazniewski M, Plewczynski D, Goral A, Soroczynska K, Domagala J, Marhelava K, Slusarczyk A, Retecki K, Ramji K, Krawczyk M, Temples MN, Sharma B, Lachota M, Netskar H, Malmberg KJ, Zagozdzon R, Winiarska M |
Cancer immunology research | 2021 |
Minimal PD-1 expression in mouse and human NK cells under diverse conditions
Sean J. Judge, Cordelia Dunai, Ethan G. Aguilar, Sarah C. Vick, Ian R. Sturgill, Lam T. Khuat, Kevin M. Stoffel, Jonathan Van Dyke, Dan L. Longo, Morgan A. Darrow, Stephen K. Anderson, Bruce R. Blazar, Arta M. Monjazeb, Jonathan S. Serody, Robert J. Canter, William J. Murphy |
Journal of Clinical Investigation | 2020 |
"Inflammescent" CX3CR1+CD57+ CD8 T-cells are generated and expanded by IL-15
Stephen R. Morris, Bonnie Chen, Joseph C. Mudd, Soumya Panigrahi, Carey L. Shive, Scott F. Sieg, Cheryl M. Cameron, David A. Zidar, Nicholas T. Funderburg, Souheil-Antoine Younes, Benigno Rodriguez, Sara Gianella, Michael M. Lederman, Michael L. Freeman |
JCI Insight | 2020 |
Age-severity matched cytokine profiling reveals specific signatures in Covid-19 patients
R Angioni, R Sánchez-Rodríguez, F Munari, N Bertoldi, D Arcidiacono, S Cavinato, D Marturano, A Zaramella, S Realdon, A Cattelan, A Viola, B Molon |
Cell Death and Disease | 2020 |
Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity
H Zhu, RH Blum, D Bernareggi, EH Ask, Z Wu, HJ Hoel, Z Meng, C Wu, KL Guan, KJ Malmberg, DS Kaufman |
Cell Stem Cell | 2020 |
IL15 Stimulation with TIGIT Blockade Reverses CD155-mediated NK-Cell Dysfunction in Melanoma
JM Chauvin, M Ka, O Pagliano, C Menna, Q Ding, R DeBlasio, C Sanders, J Hou, XY Li, S Ferrone, D Davar, JM Kirkwood, RJ Johnston, AJ Korman, MJ Smyth, HM Zarour |
Clinical cancer research | 2020 |
Analysis of Human Natural Killer Cell Metabolism
J Traba, TA Waldmann, OM Anton |
Journal of visualized experiments : JoVE | 2020 |
NK cells for cancer immunotherapy
N Shimasaki, A Jain, D Campana |
Nature Reviews Drug Discovery | 2020 |
Interleukin-15 and cancer: some solved and many unsolved questions
PF Fiore, SD Matteo, N Tumino, FR Mariotti, G Pietra, S Ottonello, S Negrini, B Bottazzi, L Moretta, E Mortier, B Azzarone |
Journal for ImmunoTherapy of Cancer | 2020 |
Inducible MyD88/CD40 synergizes with IL-15 to enhance antitumor efficacy of CAR-NK cells
X Wang, DL Jasinski, JL Medina, DM Spencer, AE Foster, JH Bayle |
Blood Advances | 2020 |
Deciphering Natural Killer Cell Homeostasis
A Pfefferle, B Jacobs, A Haroun-Izquierdo, L Kveberg, E Sohlberg, KJ Malmberg |
Frontiers in immunology | 2020 |
Metabolism of Natural Killer Cells and Other Innate Lymphoid Cells
J Cong |
Frontiers in immunology | 2020 |
Characterizing the Dysfunctional NK Cell: Assessing the Clinical Relevance of Exhaustion, Anergy, and Senescence
SJ Judge, WJ Murphy, RJ Canter |
Frontiers in Cellular and Infection Microbiology | 2020 |
Immunomodulatory Effects of IL-2 and IL-15; Implications for Cancer Immunotherapy
Y Yang, A Lundqvist |
Cancers | 2020 |
Natural Killer Cells in Immunotherapy: Are We Nearly There?
M Bachiller, AM Battram, L Perez-Amill, B Martín-Antonio |
Cancers | 2020 |
Recalling the Biological Significance of Immune Checkpoints on NK Cells: A Chance to Overcome LAG3, PD1, and CTLA4 Inhibitory Pathways by Adoptive NK Cell Transfer?
PM Lanuza, C Pesini, MA Arias, C Calvo, A Ramirez-Labrada, J Pardo |
Frontiers in immunology | 2020 |
Indirect Impact of PD-1/PD-L1 Blockade on a Murine Model of NK Cell Exhaustion
M Alvarez, F Simonetta, J Baker, AR Morrison, AS Wenokur, A Pierini, P Berraondo, RS Negrin |
Frontiers in immunology | 2020 |
Innate Cytokine Induced Early Release of IFNγ and CC Chemokines from Hypoxic Human NK Cells Is Independent of Glucose
SY Velásquez, BS Himmelhan, N Kassner, A Coulibaly, J Schulte, K Brohm, HA Lindner |
Cells | 2020 |
IL-15 in the Combination Immunotherapy of Cancer
TA Waldmann, S Dubois, MD Miljkovic, KC Conlon |
Frontiers in immunology | 2020 |
NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo
DA Vallera, S Ferrone, B Kodal, P Hinderlie, L Bendzick, B Ettestad, C Hallstrom, NA Zorko, A Rao, N Fujioka, CJ Ryan, MA Geller, JS Miller, M Felices |
Cancers | 2020 |
Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors
E Liu, D Marin, P Banerjee, HA Macapinlac, P Thompson, R Basar, LN Kerbauy, B Overman, P Thall, M Kaplan, V Nandivada, I Kaur, AN Cortes, K Cao, M Daher, C Hosing, EN Cohen, P Kebriaei, R Mehta, S Neelapu, Y Nieto, M Wang, W Wierda, M Keating, R Champlin, EJ Shpall, K Rezvani |
New England Journal of Medicine | 2020 |
Directed Differentiation of Mobilized Hematopoietic Stem and Progenitor Cells into Functional NK Cells with Enhanced Antitumor Activity
P Oberoi, K Kamenjarin, JF Ossa, B Uherek, H Bönig, WS Wels |
Cells | 2020 |
Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway
Maite Alvarez, Federico Simonetta, Jeanette Baker, Antonio Pierrini, Arielle S Wenokur, Alyssa R Morrison, William Murphy, Robert Negrin |
JCI Insight | 2019 |
Interleukin-15 (dys)regulation of lymphoid homeostasis: Implications for therapy of autoimmunity and cancer
TA Waldmann, MD Miljkovic, KC Conlon |
Journal of Experimental Medicine | 2019 |
Adipocytes: A Novel Target for IL-15/IL-15Rα Cancer Gene Therapy
R Xiao, AG Mansour, W Huang, LA Chrislip, RK Wilkins, NJ Queen, Y Youssef, HC Mao, MA Caligiuri, L Cao |
Molecular Therapy | 2019 |
NK Cell Hyporesponsiveness: More Is Not Always Better
M Frutoso, E Mortier |
International journal of molecular sciences | 2019 |
Genetic reprogramming for NK cell cancer immunotherapy with CRISPR/Cas9
LO Afolabi, AO Adeshakin, MM Sani, J Bi, X Wan |
Immunology | 2019 |
The Synergistic Use of IL-15 and IL-21 for the Generation of NK Cells From CD3/CD19-Depleted Grafts Improves Their ex vivo Expansion and Cytotoxic Potential Against Neuroblastoma: Perspective for Optimized Immunotherapy Post Haploidentical Stem Cell Transplantation
A Heinze, B Grebe, M Bremm, S Huenecke, TA Munir, L Graafen, JT Frueh, M Merker, E Rettinger, J Soerensen, T Klingebiel, P Bader, E Ullrich, C Cappel |
Frontiers in immunology | 2019 |
Immune Reconstitution Disorders: Spotlight on Interferons
IV Louis |
2019 | |
Inducing Fat to Feed a Natural Killer of Malignancy
B Rambaldi, R Romee |
Molecular Therapy | 2019 |
Strategies to Augment Natural Killer (NK) Cell Activity against Solid Tumors
Z Chen, Y Yang, LL Liu, A Lundqvist |
Cancers | 2019 |
NK Cell Metabolism and Tumor Microenvironment
I Terrén, A Orrantia, J Vitallé, O Zenarruzabeitia, F Borrego |
Frontiers in immunology | 2019 |
Harnessing Natural Killer Cell Antitumor Immunity: From the Bench to Bedside
KV Woan, JS Miller |
Cancer immunology research | 2019 |
NK Cells for PD-1/PD-L1 blockade immunotherapy- Pinning Down the NK cell
Cordelia Dunai, William Murphy |
Journal of Clinical Investigation | 2018 |
Tumor Microenvironment-Induced Immunometabolic Reprogramming of Natural Killer Cells
AM Chambers, KB Lupo, S Matosevic |
Frontiers in immunology | 2018 |
Natural killer cells as a therapeutic tool for infectious diseases - current status and future perspectives
S Schmidt, L Tramsen, B Rais, E Ullrich, T Lehrnbecher |
Oncotarget | 2018 |
IL-15 regulates fibrosis and inflammation in a mouse model of chronic pancreatitis
M Manohar, HK Kandikattu, AK Verma, A Mishra |
AJP Gastrointestinal and Liver Physiology | 2018 |
Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma
B Mundy-Bosse, N Denlinger, E McLaughlin, N Chakravarti, S Hwang, L Chen, HC Mao, D Kline, Y Youssef, R Kohnken, DA Lee, G Lozanski, AG Freud, P Porcu, B William, MA Caligiuri, A Mishra |
Blood Advances | 2018 |